The interaction of dietary components, such as the polyphenols and alcohol, on chronic diseases, particularly those of the cardiovascular system, is only recently emerging. This is a key area since considerable epidemiological evidence indicates that consumption of moderate levels of alcoholic beverages, particularly red wine, decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but appear to involve complex interactions of these components with cells in the vascular wall. The main attribute of the polyphenols that have been forwarded to explain these protective effects has been their antioxidant properties. Data forming the foundation of this proposal indicate an interesting elaboration of the hypothesis that polyphenols act as antioxidants, particularly in conjunction with ethanol. It is proposed that transcriptional regulation of the concentration and activity of critical vascular protective enzymes makes a major contribution to the enhanced cardiovascular protective effects and is more pronounced in combination with ethanol. The main effect of the enhanced endogenous cytoprotective enzymes is to increase the bioavailability of nitric oxide (NO). Preliminary data shows that dietary polyphenols and alcohol (1) enhance NO-dependent vascular function (2) increase expression of nitric oxide synthases (NOS) mRNA in the vasculature; (3) induce protein expression of both iNOS and eNOS isoforms in the vasculature; (4) induce vascular superoxide dismutases (SOD); and (5) that increased bioavail- ability of NO may be responsible for the cardiovascular protection. These data have led to the hypothesis that "moderate alcohol or dietary polyphenols will increased NO bioavailability and play a pivotal role in conferring vascular protection". This hypothesis will be tested by completion of the following Specific Aims: (1) induction of NOS by dietary polyphenols and moderate alcohol increases bioavailability of NO and results in vascular protection, (2) induction of SOD and a consequent decrease in superoxide (O2-.) by dietary polyphenols and moderate alcohol increases the bioavailability of NO and results in vascular protection, and (3) polyphenol supplementation results in vascular protection due to both increased bioavailability of NO and a consequent decreased susceptibility to pro-inflammatory oxidants. The completion of these specific aims will provide insight into the mechanisms that lead to increased NO and role that these NO-dependent mechanisms play in the cardiovascular protection associated with polyphenols and alcohol.